Application Of Fluorous Biphasic Technic In The Synthesis Of Telmisartan's Intermediates

Telmisartan is a new kind of pharmaceutical for hypertension. The studies on telmisartan focus on pharmacology and efficacy at home and abroad, while the study about it's synthesis has only received few attension.The pharmaceutical Telmisartan was synthesized by reduction, esterification, acylation, nitration, reduction, cyclation, hydrolysis, cyclation, alkylation and hydrolysis using 3-methyl-4-nitrobenzoic acid as starting material. The fluorous biphasic technology was applied in the process of esterification, nitration, and condensation. The total yield of Telmisartan was 36.3% based on 3-methyl-4-nitrobenzoic acid.The catalyst of rare earth (III) perfluorooctanesulfonates (RE(OPf)₃, RE=Sc,Y, La-Lu) were prepared from either rare earth chlorides (III) or oxides and perfluorooctanesulfonic acid, and easily accessible perfluorinated transition metal catalysts (M(OPf)_x, M= Ti-Zn, Pd, x= 2,3,4,5) were prepared. The perflates obtained were characterized by DSC, ICP, IR, and Elemental Analysis.Effects of reaction temperature, reaction time, amount and species of catalyst, amount of solvent, ratio between material were investigated for the processes such as reduction, acylation, hydrolysis and alkylation.The perflates thus acted as novel catalysts for esterification, nitration, condensation of ketone with amine in fluorous biphasic system. Perfluorohexane perfluoromethylcyclohexane (C7F14), perfluorotoluene (C7F8), perfluorooctane perfluorooctyl bromide (C₈F₁₇Br) and perfluorodecalin (C₁₀F₁₈, cis and trans-mixture) can be used as fluorous solvents for these reactions. Effects of reaction temperature, reaction time, amount and species of catalyst, species of fluorous solvent, and the ratio of fluorous phase/organic phase on these reactions were investigated. Yb(OPf)3 and C₁₀F₁₈ were the best catalyst and fluorous solvent respectively. By simple phase separation the fluorous phase containing catalyst could be re-utilized up to five times only with a little decrease in activity.